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W W Lytton

Publications and source records attributed to W W Lytton.

18 recordsLinked to original sources
PubMed1998

Computer model of antiepileptic effects mediated by alterations in GABA(A)-mediated inhibition.

Results from a computer model of a thalamic network predict that agents augmenting GABA(A)-mediated inhibition in the reticular thalamic (RE) nucleus will be antiepileptic or desynchronizing. This provides support for the hypothesis that antiepileptics like benzodiazepines may exert their effects through an isolated increase of inhibition in the RE nucleus. When desynchronized, the model thalamocortical neurons showed a decreased probability of firing a low threshold spike, a decreased secondary inhibitory postsynaptic potential and a higher frequency of oscillations. The transition to desynchrony was also accompanied by an increased frequency in the firing of the model RE neurons.

Anticonvulsants↗
PubMed1998

Computer models of hippocampal circuit changes of the kindling model of epilepsy.

Abnormalities in the organization of brain circuits may underlie many types of epilepsy. This hypothesis can best be evaluated in the case of temporal lobe epilepsy, where evidence of rewiring (synaptic reorganization) can be found in the dentate gyrus. Computer modeling of normal and reorganized dentate gyrus was used to understand the functional consequences of these structural changes. Hyperexcitability appeared to be largely limited by the powerful intrinsic adaptation characteristic of granule cells, the principal cells in this area. Combining disinhibition with new recurrent excitatory circuitry was necessary to produce repeated firing of these cells. Paradoxically, continuing regenerative activity was only seen with a large reduction in the strength of the inciting stimulus. Validation of these findings will require further physiological correlation.

Computer Simulation↗
PubMed1998

Adapting a feedforward heteroassociative network to Hodgkin-Huxley dynamics.

Using the original McCulloch-Pitts notion of simple on and off spike coding in lieu of rate coding, an Anderson-Kohonen artificial neural network (ANN) associative memory model was ported to a neuronal network with Hodgkin-Huxley dynamics. In the ANN, the use of 0/1 (no-spike/spike) units introduced a cross-talk term that had to be compensated by introducing balanced feedforward inhibition. The resulting ANN showed good capacity and fair selectivity (rejection of unknown input vectors). Translation to the Hodgkin-Huxley model resulted in a network that was functional but not at all robust. Evaluation of the weaknesses of this network revealed that it functioned far better using spike timing, rather than spike occurrence, as the code. The algorithm requires a novel learning algorithm for feedforward inhibition that could be sought physiologically.

Action Potentials↗
PubMed1997

Computer model of clonazepam's effect in thalamic slice.

In the thalamus, paradoxical changes in response to augmentation of inhibition can occur as a result of either cellular or network effects. Clonazepam, a GABA(A) agonist, produces a paradoxical reduction in evoked thalamocortical neuron inhibitory postsynaptic potential (IPSP) in thalamic slice. This has been hypothesized to be a result of augmentation in inhibitory to inhibitory connections. In a computer model, orthodromic simulation produced an increase in initial IPSP, a result contrary to that found experimentally. This failure was traced to the inability of orthodromic activation to produce fast enough recurrent inhibition to alter initial reticularis neuron firing. Simulated antidromic stimulation was able to reduce this initial spike train and reproduced the experimental finding.

Animals↗
PubMed1997

Inhibition can disrupt hypersynchrony in model neuronal networks.

1. Model neuronal network simulations were performed using a reduced Traub neuronal network model. In the absence of inhibition the network produced synchronous population bursting. 2. Bursting of individual neurons was dependent on 1 or more of the following: build-up of charge in the dendritic compartment, prolonged current flow through simulated NMDA associated channels, current flow through T channels. Interburst interval duration and consequent burst frequency was dependent on the density of slow after-hyperpolarizing potassium channels. 3. Addition of an inhibitory interneuron population projecting to GABAA receptors resulted in rapid desynchronization of the population, generally after only 1-2 cycles. This effect was found to be due to reduced participation in the individual population burst and to the need for multi-synaptic activation of the individual neuron in the presence of inhibition. 4. This desynchronizing effect could be offset by increasing the strength of interburst hyperpolarization either through increased density of IAHP, or through the addition of a separate inhibitory interneuron pool projected to GABAB receptors. 5. These data suggest that the synchronizing effects of inhibition may vary depending on circumstances-with desynchronization being dominant in cases characterized by large population bursts such as those seen in epilepsy.

Excitatory Amino Acid Agonists↗
PubMed1997

Dynamic interactions determine partial thalamic quiescence in a computer network model of spike-and-wave seizures.

In vivo intracellular recording from cat thalamus and cortex was performed during spontaneous spike-wave seizures characterized by synchronously firing cortical neurons correlated with the electroencephalogram. During these seizures, thalamic reticular (RE) neurons discharged with long spike bursts riding on a depolarization, whereas thalamocortical (TC) neurons were either entrained into the seizures (40%) or were quiescent (60%). During quiescence, TC neurons showed phasic inhibitory postsynaptic potentials (IPSPs) that coincided with paroxysmal depolarizing shifts in the simultaneously recorded cortical neuron. Computer simulations of a reciprocally connected TC-RE pair showed two major modes of TC-RE interaction. In one mode, a mutual oscillation involved direct TC neuron excitation of the RE neuron leading to a burst that fed back an IPSP into the TC neuron, producing a low-threshold spike. In the other, quiescent mode, the TC neuron was subject to stronger coalescing IPSPs. Simulated cortical stimulation could trigger a transition between the two modes. This transition could go in either direction and was dependent on the precise timing of the input. The transition did not always follow the stimulation immediately. A larger, multicolumnar simulation was set up to assess the role of the TC-RE pair in the context of extensive divergence and convergence. The amount of TC neuron spiking generally correlated with the strength of total inhibitory input, but large variations in the amount of spiking could be seen. Evidence for mutual oscillation could be demonstrated by comparing TC neuron firing with that in reciprocally connected RE neurons. An additional mechanism for TC neuron quiescence was assessed with the use of a cooperative model of gamma-aminobutyric acid-B (GABA(B))-mediated responses. With this model, RE neurons receiving repeated strong excitatory input produced TC neuron quiescence due to burst-duration-associated augmentation of GABA(B) current. We predict the existence of spatial inhomogeneity in apparently generalized spike-wave seizures, involving a center-surround pattern. In the center, intense cortical and RE neuron activity would be associated with TC neuron quiescence. In the surround, less intense hyperpolarization of TC neurons would allow low-threshold spikes to occur. This surround, an "epileptic penumbra," would be the forefront of the expanding epileptic wave during the process of initial seizure generalization. Therapeutically, we would then predict that agents that reduce TC neuron activity would have a greater effect on seizure onset than on ongoing spike-wave seizures or other thalamic oscillations.

Action Potentials↗
PubMed1997

GABAA-mediated IPSCs in piriform cortex have fast and slow components with different properties and locations on pyramidal cells.

GABAA-mediated IPSCs in piriform cortex have fast and slow components with different properties and locations on pyramidal cells. J. Neurophysiol. 78: 2531-2545, 1997. A recent study in piriform (olfactory) cortex provided evidence that, as in hippocampus and neocortex, gamma-aminobutyric acid-A (GABAA)-mediated inhibition is generated in dendrites of pyramidal cells, not just in the somatic region as previously believed. This study examines selected properties of GABAA inhibitory postsynaptic currents (IPSCs) in dendritic and somatic regions that could provide insight into their functional roles. Pharmacologically isolated GABAA-mediated IPSCs were studied by whole cell patch recording in slices. To compare properties of IPSCs in distal dendritic and somatic regions, local stimulation was carried out with tungsten microelectrodes, and spatially restricted blockade of GABAA-mediated inhibition was achieved by pressure-ejection of bicuculline from micropipettes. The results revealed that largely independent circuits generate GABAA inhibition in distal apical dendritic and somatic regions. With such independence, a selective decrease in dendritic-region inhibition could enhance integrative or plastic processes in dendrites while allowing feedback inhibition in the somatic region to restrain system excitability. This could allow modulatory fiber systems from the basal forebrain or brain stem, for example, to change the functional state of the cortex by altering the excitability of interneurons that mediate dendritic inhibition without increasing the propensity for regenerative bursting in this highly epileptogenic system. As in hippocampus, GABAA-mediated IPSCs were found to have fast and slow components with time constants of decay on the order of 10 and 40 ms, respectively, at 29 degrees C. Modeling analysis supported physiological evidence that the slow time constant represents a true IPSC component rather than an artifactual slowing of the fast component from voltage clamp of a dendritic current. The results indicated that, whereas both dendritic and somatic-region IPSCs have both fast and slow GABAA components, there is a greater proportion of the slow component in dendrites. In a companion paper, the hypothesis is explored that the resulting slower time course of the dendritic IPSC increases its capacity to regulate the N-methyl--aspartate component of EPSPs. Finally, evidence is presented that the slow GABAA-mediated IPSC component is regulated by presynaptic GABAB inhibition whereas the fast is not. Based on the requirement for presynaptic GABAB-mediated block of inhibition for expression of long-term potentiation, this finding is consistent with participation of the slow GABAA component in regulation of synaptic plasticity. The lack of susceptibility of the fast GABAA component to the long-lasting, activity-induced suppression mediated by presynaptic GABAB receptors is consistent with a protective role for this process in preventing seizure activity.

Animals↗
PubMed1997

Regulation of the NMDA component of EPSPs by different components of postsynaptic GABAergic inhibition: computer simulation analysis in piriform cortex.

Regulation of the NMDA component of EPSPs by different components of postsynaptic GABAergic inhibition: computer simulation analysis in piriform cortex. J. Neurophysiol. 78: 2546-2559, 1997. Physiological analysis in the companion paper demonstrated that gamma-aminobutyric acid-A (GABAA)-mediated inhibition in piriform cortex is generated by circuits that are largely independent in apical dendritic and somatic regions of pyramidal cells and that GABAA-mediated inhibitory postsynaptic currents (IPSCs) in distal dendrites have a slower time course than those in the somatic region. This study used modeling methods to explore these characteristics of GABAA-mediated inhibition with respect to regulation of the N-methyl--aspartate (NMDA) component of excitatory postsynaptic potentials. Such regulation is relevant to understanding NMDA-dependent long-term potentiation (LTP) and the integration of repetitive synaptic inputs that can activate the NMDA component as well as pathological processes that can be activated by overexpression of the NMDA component. A working hypothesis was that the independence and differing properties of IPSCs in apical dendritic and somatic regions provide a means whereby the NMDA component and other dendritic processes can be controlled by way of GABAergic tone without substantially altering system excitability. The analysis was performed on a branched compartmental model of a pyramidal cell in piriform cortex constructed with physiological and anatomic data derived by whole cell patch recording. Simulations with the model revealed that NMDA expression is more effectively blocked by the slow GABAA component than the fast. Because the slow component is present in greater proportion in apical dendritic than somatic regions, this characteristic would increase the capacity of dendritic IPSCs to regulate NMDA-mediated processes. The simulations further revealed that somatic-region GABAergic inhibition can regulate the generation of action potentials with little effect on the NMDA component generated by afferent fibers in apical dendrites. As a result, if expression of the NMDA component or other dendritic processes were enabled by selective block of dendritic inhibition, for example, by centrifugal fiber systems that may regulate learning and memory, the somatic-region IPSC could preserve system stability through feedback regulation of firing without counteracting the effect of the dendritic-region block. Simulations with paired inputs revealed that the dendritic GABAA-mediated IPSC can regulate the extent to which a strong excitatory input facilitates the NMDA component of a concurrent weak input, providing a possible mechanism for control of "associative LTP" that has been demonstrated in this system. Postsynaptic GABAB-mediated inhibition had less effect on the NMDA component than either the fast or slow GABAA components. Depolarization from a concomitant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) component also was found to have comparatively little effect on current through the NMDA channel because of its brief time course.

2-Amino-5-phosphonovalerate↗
PubMed1997

Receptive field changes after strokelike cortical ablation: a role for activation dynamics.

The reorganization of neural activity that takes place after stroke is of paramount importance in producing functional recovery. Experimental stroke models have suggested that this reorganization may have two phases, but physiology alone cannot fully resolve what causes each phase. Computer modeling suggests that these phases might involve an initial change in dynamics occurring immediately, followed by synaptic plasticity. We combined physiological recording from macaque middle temporal cortex (area MT) with a neural network computer model to examine this first phase of altered cortical function after a small, experimentally induced cortical lesion. Major receptive field (RF) changes seen in the first few days postlesion included both expansion and contraction of receptive fields. Although only expansion could be reproduced in an initial model, addition of inhibitory interneuron loss in a ring around the primary ablation, suggested by immunohistochemical examination, permitted contraction to be replicated as well. We therefore predict that this immunochemical observation reflects an immediate extension of the lesion rather than a late response. Additionally our model successfully predicted a correlation between increased firing rate and RF size. Our model suggests that activation dynamics alone, without anatomic remodeling, can cause the large receptive field changes that allow the rapid behavioral recovery seen after middle temporal lesions.

Animals↗
PubMed1996

Optimizing synaptic conductance calculation for network simulations.

High computational requirements in realistic neuronal network simulations have led to attempts to realize implementation efficiencies while maintaining as much realism as possible. Since the number of synapses in a network will generally far exceed the number of neurons, simulation of synaptic activation may be a large proportion of total processing time. We present a consolidating algorithm based on a recent biophysically-inspired simplified Markov model of the synapse. Use of a single lumped state variable to represent a large number of converging synaptic inputs results in substantial speed-ups.

Algorithms↗
PubMed1996

Control of slow oscillations in the thalamocortical neuron: a computer model.

We investigated computer models of a single thalamocortical neuron to assess the interaction of intrinsic voltage-sensitive channels and cortical synaptic input in producing the range of oscillation frequencies observed in these cells in vivo. A morphologically detailed model with Hodgkin-Huxley-like ion channels demonstrated that intrinsic properties would be sufficient to readily produce 3 to 6 Hz oscillations. Hyperpolarization of the model cell reduced its oscillation frequency monotonically whether through current injection or modulation of a potassium conductance, simulating the response to a neuromodulatory input. We performed detailed analysis of highly reduced models to determine the mechanism of this frequency control. The interburst interval was controlled by two different mechanisms depending on whether or not the pacemaker current, IH, was present. In the absence of IH, depolarization during the interburst interval occurred at the same rate with different current injections. The voltage difference from the nadir to threshold for the low-threshold calcium current, IT, determined the interburst interval. In contrast, with IH present, the rate of depolarization depended on injected current. With the full model, simulated repetitive cortical synaptic input entrained oscillations up to approximately double the natural frequency. Cortical input readily produced phase resetting as well. Our findings suggest that neither ascending brainstem control altering underlying hyperpolarization, nor descending drive by repetitive cortical inputs, would alone be sufficient to produce the range of oscillation frequencies seen in thalamocortical neurons. Instead, intrinsic neuronal mechanisms would dominate for generating the delta range (0.5-4 Hz) oscillations seen during slow wave sleep, whereas synaptic interactions with cortex and the thalamic reticular nucleus would be required for faster oscillations in the frequency range of spindling (7-14 Hz).

Cerebral Cortex↗
PubMed1992

Computer model of ethosuximide's effect on a thalamic neuron.

Ethosuximide appears to have a specific effect on the low-threshold calcium current in thalamic cells. This may be related to its efficacy in the treatment of absence epilepsy. We used a computer model of an individual thalamocortical neuron to better understand the alteration in the low-threshold calcium current under voltage clamp and to predict response to current injection in the presence of ethosuximide. The full model included nine voltage-sensitive ionic channels and a realistic dendritic morphology. The model reproduced the two major responses seen in tissue slices: repetitive spiking with depolarization and the low-threshold calcium spike elicited on release from hyperpolarization. The alteration in low-threshold calcium current with ethosuximide can be explained by a 10-mV depolarizing shift in the steady-state activation curve for this channel with a 10% reduction in maximum channel permeability. Simulations of current injection showed that ethosuximide diminished the low-threshold calcium spike while leaving the tonic firing pattern unaffected. Our results support the hypothesis that ethosuximide's effects on low-threshold calcium current might selectively alter the dynamics of slow bursting in thalamic cells.

Action Potentials↗
PubMed1992

Computer simulations of EPSP-spike (E-S) potentiation in hippocampal CA1 pyramidal cells.

Long-term potentiation of hippocampal excitatory synapses is often accompanied by an increase in the probability of spiking to an EPSP of fixed strength (E-S potentiation). We used computer simulations of a CA1 pyramidal neuron to test the plausibility of the hypothesis that E-S potentiation is caused by changes in dendritic excitability. These changes were simulated by adding "hot spots" of noninactivating voltage-sensitive Ca2+ conductance to various dendritic compartments. This typically caused spiking in response to previously subthreshold synaptic inputs. The magnitude of the simulated E-S potentiation depended on the passive electrical properties of the cell, the excitability of the soma, and the relative locations on the dendrites of the synaptic inputs and hot spots. The specificity of the simulated E-S potentiation was quantified by colocalizing the hot spots with a subset (40 of 80) of the synaptic contacts, denoted "tetanized," and then comparing the effects of the hot spots on these and the remaining (untetanized) synaptic contacts. The simulated E-S potentiation tended to be specific to the tetanized input if the untetanized contacts were, on average, electrically closer to the soma than the tetanized contacts. Specificity was also high if the tetanized and untetanized contacts were segregated to different primary dendrites. The results also predict, however, that E-S potentiation by this mechanism will appear to be nonspecific (heterosynaptic) if the synapses of the untetanized input are sufficiently far from the soma relative to the tetanized synapses. Experimental confirmation of this prediction would support the hypothesis that changes in postsynaptic excitability can contribute to hippocampal E-S potentiation.

Animals↗
PubMed1991

Simulations of a phase comparing neuron of the electric fish Eigenmannia.

1. Investigations of the jamming avoidance response in the weakly electric fish Eigenmannia have shown that the 'small cell', an identified cell type in lamina 6 of the torus semicircularis, can distinguish a brief time difference between the phase of externally applied sinusoidally varying electrical fields. Computer simulations were performed to determine what physiological and anatomical features of the small cell could permit this. 2. The small cell shows apparent inhibition despite having no identified inhibitory synaptic input. This effect was produced in the model using voltage-sensitive membrane channels. These permit an initial sub-threshold excitatory post-synaptic potential (EPSP) to increase the threshold to firing, preventing a subsequent EPSP from firing the cell. 3. Noise and conduction failure appeared to improve the range of cell responsivity. The addition of noise permitted a gradual change in cell firing with change in time disparity, allowing the cell to signal more subtle changes in disparity at the expense of decreased selectivity for a specific absolute time disparity. 4. The cell's multiple dendrites permit a 47% reduction in jitter for incoming signals. Other aspects of dendrite organization did not appear to contribute to the cell's precision.

Animals↗
PubMed1991

Simulations of cortical pyramidal neurons synchronized by inhibitory interneurons.

1. The interaction between inhibitory interneurons and cortical pyramidal neurons was studied by use of computer simulations to test whether inhibitory interneurons could assist in phase-locking postsynaptic cells. Two models were used: a simplified model, which included only 3 membrane channels, and a detailed 11-channel model. 2. The 11-channel model included most of the ion channels known to be present in neocortical pyramidal neurons as well as calcium diffusion and other membrane mechanisms. The kinetics for the channels were obtained from voltage-clamp studies in a variety of preparations. The parameters were then adjusted to produce repetitive bursting similar to that seen in some cortical pyramidal cells entrained during visual stimulation. 3. Phase-locking to a train of inhibitory postsynaptic potentials (IPSPs) located on or near the soma was observed in the 3-channel model cell subjected to random synaptic bombardment. In the 11-channel model, phase-locking due to multiple IPSPs was compared with phase-locking due to multiple excitatory postsynaptic potentials (EPSPs). Phase-locking began to occur when 20% of the IPSPs (20/100) or 40% of the EPSPs (4,000/10,000) were synchronized. The exact percentages differed with different 11-channel models, but either EPSPs or IPSPs would generally produce entrainment with approximately 40% synchronization. Thus 40 inhibitory boutons had an effect equivalent to 4,000 excitatory boutons in producing phase-locking. 4. Phase-locking with IPSPs in these models was possible because the IPSPs could cause either an increase or a decrease in firing rate over a limited range. The IPSPs served a modulatory role, increasing the rate of firing in some cases and decreasing it in others, depending on the state of the cell. 5. We examined frequency entrainment by IPSPs. In the 3-channel model, frequency entrainment of a postsynaptic cell was observed with a rapid train of strong (20-100 nS), brief, compound IPSPs. A 40-Hz compound IPSP train of 60 nS entrained cells having initial firing rates between 32 and 47 Hz. Below this range, cells could be partially entrained. Above the range, entrainment would fail. Frequency entrainment in the 3-channel model generally occurred on the first cycle after onset of the IPSPs. 6. Phase-locking and frequency entrainment were less robust in the 11-channel model. This was partly because bursts rather than individual spikes were being entrained. A 40-Hz, 90-nS compound IPSP train entrained a model cell upward from 34 Hz. Downward frequency entrainment also occurred.(ABSTRACT TRUNCATED AT 400 WORDS)

Calcium Channels↗
PubMed1989

Localization of a leech inhibitory synapse by photo-ablation of individual dendrites.

An inhibitory motor neuron (cell 1) in the leech nervous system has a powerful inhibitory connection onto an excitatory motor neuron (cell 3) that is functionally important in behaviours such as swimming and local bending. The anatomical location of this connection was explored using focal ultraviolet irradiation of cell 3 dendrites filled with Lucifer yellow. Ablation of the main neurite of cell 3 in the middle of the ganglion eliminated 72% of the inhibitory postsynaptic potential (IPSP), showing that most of the synaptic contacts are in the dendritic field contralateral to the cell body. Ablation of a particular dendritic branch (d1), one of several that run anteriorly from the main neurite in the contralateral ganglion, eliminated 70% of the IPSP in some cases but only 4% in others. In these latter cases, subsequent ablation of a more distal dendrite (d2) eliminated from 41% to 83% of the IPSP. These findings suggest that the synapses onto cell 3 from cell 1 are primarily mediated by either one of these dendrites or the other, but not both. This synaptic specificity might be due to a developmental mechanism involving competition between dendrites for occupation of synaptic sites.

Action Potentials↗
PubMed1989

Direct dyslexia. Preserved oral reading of real words in Wernicke's aphasia.

A 70-yr-old man was able to read aloud, without comprehending what he read, following a stroke that caused Wernicke's aphasia with severely impaired comprehension of speech. Tested on admission, and at 3 and 9 months, he could read aloud both orthographically simple and orthographically complex real words, and showed neither semantic errors, preference for nouns, nor difficulty with function words. He could not, however, read aloud orthographically simple nonwords. His disorder thus appears to be the first pure example of 'direct dyslexia', which, in contrast to previously well-documented examples of 'deep' and 'surface' dyslexia, implies the existence in reading of a direct route, independent of phonology or semantics, between visual and oral word representations.

Aged↗